Compositions and their uses directed to acetyl-CoA carboxylases
View Patent ↗Disclosed herein are compounds, compositions and methods for modulating the expression of ACC1 or ACC2 or both in a cell, tissue or animal. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders.
1. A method of ameliorating or lessening the severity of a metabolic disorder in an animal, comprising administering to the animal an antisense oligonucleotide consisting of 12 to 50 linked nucleosides, wherein the antisense oligonucleotide is at least 85% complementary to human ACC1, human ACC2, or both human ACC1 and human ACC2, wherein expression of the ACC1, the ACC2, or both the ACC1 and ACC2 is reduced, and wherein administering the antisense oligonucleotide to the animal ameliorates or lessens the severity of the metabolic disorder in the animal.
2. The method of claim 1 , wherein the reduction of ACC1, ACC2 or both ACC1 and ACC2 expression does not occur in the pancreas or CNS.
3. The method of claim 1 , wherein the reduction of ACC1, ACC2 or both ACC1 and ACC2 expression does not cause hyperphagia or inhibition of insulin secretion.
4. The method of claim 1 , wherein the antisense oligonucleotide comprises a first region comprising deoxynucleotides and a second and third region comprising 2′-O-(2-methoxyethyl)oligonucleotides.
5. The method of claim 1 , wherein administering the antisense oligonucleotide lowers blood glucose, plasma triglycerides, plasma cholesterol, or liver triglycerides levels in an animal.
6. The method of claim 1 , wherein administering the antisense oligonucleotide improves insulin sensitivity in an animal.
7. The method of claim 1 , wherein administering the antisense oligonucleotide reduces adiposity in an animal.
8. The method of any one of claims 5 , 7 , wherein ACC1, ACC2, or both ACC1 and ACC2 expression is not reduced in the CNS or pancreas.
9. The method of claim 1 , wherein ACC1 expression is reduced.
10. The method of claim 1 , wherein ACC2 expression is reduced.
11. The method of claim 1 , wherein the antisense oligonucleotide is 12 to 30 nucleobases in length and targeted to a nucleic acid molecule encoding human ACC1.
12. The method of claim 11 , wherein the oligonucleotide comprises at least one chemical modification selected from a modified internucleoside linkage, a modified nucleobase, or a modified sugar.
13. The method of claim 11 , wherein said oligonucleotide is a chimeric oligonucleotide having a first region comprising deoxynucleotides and a second and third region comprising 2′-O-(2-methoxyethyl)nucleotides.
14. The method of claim 11 , wherein the oligonucleotide comprises at least one modified internucleoside linkage.
15. The method of claim 11 , wherein the oligonucleotide comprises at least one 5-methylcytosine.
16. The method of claim 1 , wherein the oligonucleotide is 12 to 30 nucleobases in length and targeted to a nucleic acid molecule encoding human ACC2.
17. The method of claim 16 , wherein the oligonucleotide comprises at least one chemical modification selected from a modified internucleoside linkage, a modified nucleobase, or a modified sugar.
18. The method of claim 16 , wherein said oligonucleotide is a chimeric oligonucleotide having a first region comprising deoxynucleotides and a second and third region comprising 2′-O-(2-methoxyethyl)nucleotides.
19. The method of claim 16 , wherein the oligonucleotide comprises at least one modified internucleoside linkage.
20. The method of claim 16 , wherein the oligonucleotide comprises at least one 5-methylcytosine.
21. The method of claim 1 , wherein the antisense oligonucleotide is a chimeric oligonucleotide.
22. The method of claim 1 , wherein the antisense oligonucleotide comprises at least one modified nucleobase.
23. The method of claim 1 , wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.
24. The method of claim 22 , wherein the modified nucleobase comprises at least one 5-methylcytosine.
25. The method of claim 23 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
26. The method of claim 1 , wherein at least one nucleoside comprises a modified sugar.
27. The method of claim 26 , wherein at least one modified sugar is a bicyclic sugar.
28. The method of claim 26 , wherein at least one modified sugar is a 2′-O-methoxyethyl.
29. The method of claim 1 , wherein the antisense oligonucleotide is at least 90% complementary to human ACC1, human ACC2, or both human ACC1 and human ACC2.
30. The method of claim 1 , wherein the antisense oligonucleotide is 100% complementary to human ACC1, human ACC2, or both human ACC1 and human ACC2.
31. The method of claim 1 , wherein ACC1 and ACC2 expression is reduced.
32. The method of claim 1 , wherein the disorder is obesity.
33. The method of claim 1 , wherein the disorder is diabetes.
34. The method of claim 1 , wherein the disorder is insulin resistance.
35. The method of claim 1 , wherein the disorder is insulin deficiency.
36. The method of claim 1 , wherein the disorder is hypercholesterolemia.
37. The method of claim 1 , wherein the disorder is hyperglycemia.
38. The method of claim 1 , wherein the disorder is hypertriglyceridemia.
39. The method of claim 1 , wherein the disorder is hyperfattyacidemia.
40. The method of claim 1 , wherein the disorder is liver steatosis.
41. The method of claim 1 , wherein the disorder is metabolic syndrome.